The Role of BRAF Mutation in Thyroid Cancer Invasion

描述(申请人提供)：BRAF突变在甲状腺癌侵袭中的作用：甲状腺癌是一种常见的恶性肿瘤，发病率很高。分化良好的甲状腺癌是最常见的内分泌恶性肿瘤，在女性确诊的癌症中排名第七。甲状腺癌发病率在过去几十年不断上升，反映在2009年预计的37000个新病例中。虽然大多数分化良好的甲状腺癌患者的病情有限，经初步治疗后无病可医，但20%的甲状腺癌患者有局部或区域复发，5%的患者发生远处转移。已有研究证实BRAF基因是甲状腺乳头状癌中最常见的突变基因，该通路的激活导致ERK易位和下游转录失调。这种突变与侵袭性亚型的启动和进展有关，如Tall细胞，以及那些有甲状腺外扩展、淋巴结和远处转移的亚型。此外，它还与放射性碘亲和力丧失和癌症复发有关。这种突变导致入侵和远距离传播的机制尚不完全清楚。我们最近进行了一项详细的基因集浓缩分析，以分析带有或不带有这种BRAF突变的乳头状甲状腺癌患者的基因组特征。我们发现BRAFV600E突变会导致几种细胞黏附分子的改变，包括凝血酶反应蛋白-1、整合素和其他基质活性蛋白，如基质金属蛋白酶。在这里，我们假设BRAF突变和这些黏附分子的变化在最具侵袭性和不可治愈的乳头状甲状腺癌的侵袭和转移中起关键作用。此外，我们推测，选择性BRAF抑制剂目前正在几种癌症中得到验证，可以用于治疗携带BRAF突变的甲状腺癌。我们的目标是研究BRAF V600E突变的作用，以及BRAF诱导的TSP-1、基质金属蛋白酶和其他ECM分子在甲状腺癌细胞系中的表达，以及一种新的临床前甲状腺癌小鼠模型。我们还计划测试BRAFV600E特异性抑制剂的有效性，并确定TSP-1和MMPs是否可以用作诊断甲状腺癌侵袭性形式的生物标志物，以及评估BRAF抑制剂的疗效的治疗性生物标志物。

DESCRIPTION (provided by applicant): Role of BRAF mutation in thyroid cancer invasion: Thyroid cancer is a common malignancy associated with substantial morbidity. Well-differentiated thyroid cancer is the most common endocrine malignancy and ranks as the seventh most common cancer diagnosed in women. Increasing incidence of thyroid cancer over the past few decades is reflected by the projected 37,000 new cases in 2009. While the majority of patients with well-differentiated thyroid cancer presents with limited disease and become disease-free after initial treatment, 20% of patients with thyroid cancer have local or regional recurrent disease, and 5% develop distant metastases. Prior studies have identified the BRAF gene as the most commonly mutated in papillary thyroid cancer, activation of this pathway leads to ERK translocation and downstream transcriptional dysregulation. This mutation is implicated in the initiation and progression of aggressive subtypes such as tall cell, and in those with extra-thyroidal extension, lymph nodal and distant metastases. Moreover, it is associated with both loss of radioiodine avidity and cancer recurrence. The mechanisms by which this mutation induces invasion and distant spread are not fully understood. We have recently carried out a detailed Gene Set Enrichment Analysis to analyze the genomic signature of papillary thyroid cancer patients with or without this BRAF mutation. We have found that BRAFV600E mutation results in the alteration of several cell adhesion molecules including Thrombospondin-1, integrins and other stromally active proteases, such as matrix metalloproteases. Here we posit that BRAF mutation and changes in these adhesion molecules plays a crucial role in the invasion and metastasis of the most aggressive and non-curable forms of papillary thyroid cancer. In addition, we postulate that selective BRAF inhibitors that are currently being validated in several forms of cancer could be utilized in the treatment of the thyroid cancers harbouring BRAF mutation. Our goal is to characterize the role of BRAF V600E mutation, as well as BRAF induced expression of TSP-1, matrix metalloproteases and other ECM molecules in thyroid cancer cell lines, as well as a novel preclinical mouse model of thyroid cancer. We also plan to test the efficacy of BRAFV600E specific inhibitors and to determine whether TSP-1, and MMPs could be utilized as a diagnostic biomarker for detection of the aggressive forms of thyroid cancer as well as therapeutic biomarkers to evaluate the response to BRAF inhibitors.